University Of California Los Angeles

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY/ABSTRACT Gestational diabetes mellitus (GDM), one of the most common and growing complications in pregnancy, presents striking racial and ethnic disparities. Asian American women are twice as likely to have GDM as non- Hispanic White women and there is also substantial heterogeneity in GDM rates across Asian subpopulations. The molecular mechanisms and upstream determinants for the high and heterogeneous risk of GDM across Asian subpopulations remain largely understudied since they are under-represented in health research. As one of the fastest-growing racial and ethnic groups in the US, it is crucial to better understand the molecular differences and similarities across Asian subpopulations to help elucidate the pathophysiology underlying their high and heterogeneous risk of GDM. Metabolomics is a powerful tool for comprehensively evaluating global metabolic signatures and understanding biological pathways. However, metabolomics studies among pregnant individuals are still limited and most have no or few Asian Americans. This study aimed to fill the current data and knowledge gaps for GDM disparity research by using a highly cost-efficient design that leverages the existing and unique resources: the California (CA) Alpha-fetoprotein Screening Program (CA-AFSP) and the Pregnancy Environment and Lifestyle Study (PETALS). In the discovery sample from the CA-AFSP program which covers >74% of the pregnant individuals in Southern CA, we propose to perform integrated untargeted and targeted metabolomic profiling using stored serum samples collected in early-mid pregnancy (15-19 gestational weeks) from 1500 individuals of four Asian subpopulations (i.e., 375 each of Chinese, Filipinos, Indian, and Vietnamese). We will identify metabolomic signatures in early-mid pregnancy associated with GDM in the CA-AFSP program and determine which metabolites and pathways overlap across all Asian Americans or distinguish across Asian subpopulations (Aim 1). We will construct an external validation set from the above four Asian subpopulations who participated in the PETALS cohort at Kaiser Permanente Northern CA. The PETALS is a well-characterized cohort with anthropometrics, multi-domain survey data, comprehensive health data from state-of-the-art electronic health records, and serum metabolomics assessed at 16-19 gestational weeks. We will validate GDM- related metabolomic signatures in the PETALS cohort for all Asian Americans and each Asian subpopulation (Aim 2) and examine associations of upstream lifestyles and social determinants of health (SDOHs) with GDM risk and metabolic signatures and whether metabolomic signatures partially mediate the association between upstream lifestyles and SDOHs with GDM risk (Aim 3). As the largest-scale study to date, our integrative approach encompassing metabolomics, lifestyles, and SDOHs provides an unparalleled opportunity to elucidate mechanisms of the drastic racial and ethnic disparities in GDM and to inform precision preventions for the high- risk, heterogeneous Asian subpopulations. Thus, this study has the potential to improve minority health and health equality in our nation.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract Impaired social motivation, or “asociality,” is a negative symptom of schizophrenia and a cause of significant functional impairment in the illness. Whereas many symptoms of schizophrenia can be treated with antipsychotic medications, deficits in social motivation persist, leading to significant social disability in patients. There is currently no effective treatment for this symptom of the illness. One promising and unexplored avenue to enhance social motivation in schizophrenia is ± 3,4-methylenedioxymethamphetamine (MDMA). MDMA is a psychostimulant that shares some pharmacological properties with amphetamines, but in addition, has pronounced pro-social effects, increasing the motivation to engage socially. In healthy volunteers, it produces feelings of empathy and closeness with others and increases attention to positive social cues, perhaps partly through its effects on the social bonding hormone, oxytocin. MDMA has shown promise in other psychiatric conditions such as PTSD. Thus, MDMA could offer a unique therapeutic benefit in patients with schizophrenia who suffer from impaired social motivation. We plan to test the hypothesis that MDMA enhances social motivation in patients with schizophrenia by conducting a two-phase study. The first phase (Aim 1) will be an open-label, ascending-dose, within-subject trial in which participants will receive 40mg, 80mg, or 120mg of MDMA. The doses will be administered in ascending order, but doses will be stopped if subjects experience moderate or greater psychotic symptoms at 24 hours. This trial will assess the tolerability of the drug in this population and guide in the selection of a maximum well-tolerated dose for the second phase. The primary tolerability measure will be clinician-rated psychotic symptoms (disorganized speech, delusions, hallucinations) collected at 24 hours after MDMA administration. Phase 2 (Aim 2) will be a randomized, placebo-controlled trial using a crossover design to test the acute effects of MDMA on social motivation and plasma oxytocin in patients with schizophrenia. Social motivation will be assessed using a social attention bias task (ABT), which has been validated in MDMA trials with healthy volunteers, in addition to secondary behavioral and self-report measures of social motivation. The results of this project will lay the foundation for further investigations of MDMA and other psychoactive compounds as a treatment for debilitating and difficult-to-treat social deficits in schizophrenia. Future studies will examine interactions between the effects of psychoactive compounds and nonpharmacologic psychosocial interventions targeting social symptoms.

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY / ABSTRACT Treatments for plaque psoriasis vary substantially in effectiveness and side effects. It is often difficult to determine the optimal treatment during a patient-centric, shared decision-making process between the clinician and patient. The NIH and other stakeholders consider patient-reported outcomes (PROs) crucial for the support of patient-centered care because PROs reflect the patients’ perspective and offer important information to improve clinical decision-making and care delivery. Treatment satisfaction is a key PRO that represents the patient’s experience with the process and outcome of the treatment. Patient satisfaction with their treatment is critical because it affects patients’ treatment- related behaviors, such as the likelihood of continuing to use their medication, to use the medication correctly, and to adhere to prescribed treatment regimens. These treatment-related behaviors, in turn, substantially impact the success of treatment outcomes. The overarching goal of this study is to validate a patient-reported, dermatology-specific treatment satisfaction instrument (DermSat). In this study, we plan to achieve two aims. In Aim 1, we will validate DermSat for longitudinal assessment of patient satisfaction with psoriasis treatments during stable psoriasis and flares. We will also determine if DermSat will confer good reliability. We will study this aim in a prospective, observational cohort and recruit from a diverse psoriasis patient population in southern California. In Aim 2, we will determine whether DermSat predicts medication adherence and treatment changes. Specifically, we will evaluate the predictive validity of DermSat by examining the relationship between DermSat and subsequent assessment of adherence and treatment changes. A measure with excellent predictive validity will enable clinicians to identify treatment dissatisfaction and intervene earlier to minimize the long-term impact of psoriasis. The successful completion of this research will lead to the first valid and reliable dermatology-specific treatment satisfaction instrument. The study findings will have a marked impact on future clinical trial design. DermSat will address the critical need to capture patients’ treatment experience in studies for both approved and investigative dermatological therapies. Valid assessment of patients’ treatment satisfaction will also help inform shared decision-making between clinicians and patients in clinical practice, predict treatment adherence, and improve the likelihood of long-term treatment success.

NIH Research Projects · FY 2025 · 2023-09

The burden of stroke among US adults is the fifth leading cause of death and the leading cause of disability, costing an estimated $19 billion. Additionally, one-quarter of strokes that occur each year in the U.S. are recurrent events.78 A large, U.S. and U.K. multicenter trial focused on cardiovascular event recurrence evaluated 3,470 recent stroke patients and followed them for 2 years.81 African-American (AA) patients with recent stroke had an 60% higher risk of recurrent stroke compared to the general population.81 This difference was explained by substantially greater vascular risk in the AA patients and suggested that scientifically justified and targeted risk factor control post-stroke could improve heath outcomes among individuals at the very highest risk of stroke. The proposed project will test a curriculum-guided self-management support approach, TargEted MAnageMent (TEAM) focused specifically on high-risk men who have had cardiovascular events (stroke or transient ischemic attack/TIA). The project builds upon promising pilot data from 2 previous R21 projects. Novel project aspects include the: 1) Focus on high-risk men, 2) Use of Peer Dyads (stroke survivors and their care partners) as a key intervention component, 3) Use of curriculum-driven self-management, and 4) Investigation of mechanistic factors that may help explain the most salient experimental elements of TEAM. The proposed project is a 6-month prospective randomized controlled trial evaluating the effects of TEAM vs. wait-list (WL) control in high-risk men who have experienced a stroke or TIA within the past 10 years. The primary outcome is change in systolic BP, while secondary outcomes include diastolic BP, cholesterol, triglycerides and glycemic control for individuals with diabetes. An exploratory analysis will evaluate posited mechanistic attitudinal targets (stroke knowledge, self-efficacy, perceived social support) as well as proximal behaviors to reduce stroke risk including diet, exercise, smoking, and tobacco/substance use. A complementary qualitative assessment will evaluate the perspective of TEAM and WL participants. If pilot results can be confirmed, TEAM represents a practical approach suitable for broad scale-up to reduce the burden of stroke among individuals who are at high risk of experiencing a stroke event.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Detecting cancer early is the best way to fight against cancer. The development of the Multi-Cancer Early Detection (MCED) liquid biopsy tests holds great promise for integrating early cancer detection into routine clinical care. However, the current MCED tests have unsatisfactory performance for early-stage cancers. Recently, we have developed a sensitive and cost-effective technology, named cell-free DNA Methylome Sequencing (cfMethyl-Seq), which uses the cell-free DNA methylome for early cancer detection. cfMethyl-Seq provides >12-fold enrichment over whole genome bisulfite sequencing in CpG islands. We performed the proof- of-principle study by applying cfMethyl-seq to a cohort of colon, liver, lung, and stomach cancer patients and controls, and obtained promising results in detecting and locating these cancer types. Here, we will further improve the cfMethyl-seq technology and apply it to detect and locate colon, gastric, liver, and lung cancer. We will validate this MCED test in multiple clinical cohorts. Our multidisciplinary team proposes the following aims: (1) Continued improvement of the cfMethyl-seq assay for early cancer detection. (2) Continued improvement of our computational method to analyze the cfDNA methylome assay data. (3) Clinically validate the cfDNA Methylome assay as an MCED assay with colon/gastric/liver/lung cancers as the first indications. (4) Contribute to Collaborative Trans-consortium Activities. We have a long-standing collaboration with the industry partner, EarlyDiagnostics, which will optimize the cfMethyl-seq assay to facilitate its clinical adoption and implement the computational algorithm in a secure cloud computing platform to facilitate data sharing and decentralized testing.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract Implementing effective prehospital medical care could prevent over half of injury-related deaths. As a first step toward development of prehospital care systems, several low- and middle-income countries (LMIC) in sub- Saharan Africa (SSA) have instituted lay first responder (LFR) programs training non-medical professionals with high exposure to injury in first aid and safe transport of injured patients. Although promising, lack of research infrastructure and medical records in SSA has limited prior evaluation of the feasibility and effectiveness of LFR implementation in increasing quality prehospital care. Cameroon is disproportionately affected by injury and lacks a prehospital care system, likely contributing to treatment delays and preventable morbidity and mortality. Development of a lay first responder program could increase access to prehospital care and facilitate timely treatment of injuries but only if it is feasible and effective for the Cameroonian context. The long-term goal of this research is to reduce the burden associated with injury in Cameroon. This study’s overall objective is to increase access to quality prehospital trauma care in Cameroon by using an implementation science approach to develop and evaluate a data-driven LFR program in Cameroon. The study hypothesis is that is implementation of a data-adapted lay first responder program is a feasible and effective method of increasing access to prehospital care among injured Cameroonian patients. To accomplish our objective, this study will pursue three specific aims: 1) Develop a Cameroon-adapted LFR program using a two-stage, mixed-methods approach; 2) Evaluate feasibility of LFR program implementation in the Cameroonian context; and 3) Evaluate effectiveness of LFR program implementation in the Cameroonian context. Validating LFR as a feasible means to increase access to prehospital care will remove a major roadblock in delivering timely trauma care and provide a critical target for reducing the detrimental impact of injury on this population. Understanding associations between LFR implementation, physiologic parameters and outcomes will allow data-informed, iterative improvement of LFR training. Development of a reproducible method for context-adaptation of LFR could be rapidly scaled for wider implementation throughout Cameroon and validated in other LMIC contexts and sectors.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY Repetitive transcranial magnetic stimulation (rTMS) is noninvasive method for brain stimulation and is an FDA- approved treatment for major depression and obsessive compulsive disorder. It also shows promise in treating numerous other neurological and psychiatric disorders. High frequency (HF) rTMS targeting prefrontal cortex (PFC), the original and most widely used paradigm, is thought to exert its therapeutic effects by enhancing cortical excitability. However, clinical outcomes following HF-rTMS treatment are variable, and the detailed mechanisms of action are not known. Previous mechanistic studies have been limited by a lack of established animal models of rTMS with strong face validity. Our lab has acquired the first rodent TMS coil capable of generating focal, suprathreshold stimulation of individual cortical regions in the rodent brain. I will use this coil to determine how in vivo chronic HF-rTMS modifies prefrontal excitatory neurons and which projection classes underlie improved behavioral outcomes. By combining rTMS with cutting edge neuroscience tools, I will test the hypothesis that HF-rTMS specifically induces structural plasticity in intratelencephalic (IT) circuits and that activation of these circuits underlies HF-rTMS-induced changes in behavior. In Aim 1, I will determine how and where chronic HF-rTMS induces synaptic changes by using sparse fluorescent labeling of excitatory neurons in PFC to quantify dendritic spine density. In Aim 2, I will use chemogenetic approaches to determine whether subclasses of prefrontal neurons underlie behavioral effects of HF-rTMS. This proposal addresses a pressing need to understand which circuits mediate the effects of HF-rTMS on behavior. This research will inform the rational design of more effective rTMS treatments that precisely target specific deficits underlying the pathophysiology of psychiatric disorders.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Phages are viruses that infect bacteria, and are the most abundant type of organism on earth. In addition, phages are a potential antibacterial therapy. The overall focus of the project is phage- inspired engineering for antibacterial applications and fundamental evolutionary studies. The first goal is to develop phage-based nanomaterials for technologies targeting bacteria. We have previously engineered synthetic phages to deliver colloidal gold, which creates intense heat when exposed to light. These targeted nanomaterials may be effective for treating bacterial infections. However, engineering them to target a specific bacterial pathogen is an important challenge that is addressed in this proposal. Second, phages are an excellent platform for evolutionary studies, as peptides displayed on their surfaces can exhibit various functions. Based on our previous experience with mapping fitness landscapes, we propose systematic studies to map the complete fitness landscape of phage-displayed peptides and probe their evolvability. Third, to improve efficacy and overcome problems with immunogenicity of phages, we propose encapsulation in lipid nanoparticles as an alternative approach for carrying and delivering colloidal gold to a target. Our approaches combine emerging synthetic technologies, growing metagenomic databases, and advances in empirical studies of evolution.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY/ABSTRACT Exposure to toxic organophosphorus (OP) compounds in the form of insecticides or chemical warfare nerve agents (CWNAs) remains a persistent concern for both civilian and military populations. One countermeasure to OP exposure that has been shown to be effective in animal models is the use of intravenously administered butyrylcholinesterase (BChE), which scavenges free OP molecules in the bloodstream. A significant limitation of BChE, however, is that it simply binds OP compounds stoichiometrically, resulting in the inactivation of both molecules. The resulting requirement for large doses of BChE is exacerbated by difficulties associated with its manufacture, thereby complicating its use as an OP defense measure. An important advance would therefore be the modification of the human BChE enzyme to enable catalytic degradation of OP compounds, thus providing a therapeutic enzyme with minimal potential immunogenicity. Several lines of evidence support the feasibility of this approach: microbial enzymes that exhibit high OP hydrolysis activity are known, and studies by our lab and others have shown that BChE can be made modestly catalytic for OP hydrolysis through the introduction of mutations or by adding certain oxime compounds. With this in mind, our ultimate goal is to develop catalytic human BChE enzymes that can functionally mimic microbial or oxime-coupled OP degradation reactions, but which also exhibit long serum half-lives, negligible side effects, and minimal immunogenicity. A critical and novel aspect of our work is the rational introduction of a zinc-binding site within the substrate gorge of the BChE enzyme, which is designed to mimic the catalytic center of the highly efficient bacterial organophosphate hydrolase (OPH) and other engineered hydrolytic zinc enzymes. Three basic design strategies are described for initial evaluation, while additional and subsequent optimized mutants will be developed through multiscale computer-guided design. BChE mutants will be expressed in HEK293E cells, which we have successfully used to produce properly glycosylated BChE tetramers in quantities sufficient for characterization. Evaluation of the metal binding site will be assessed through spectroscopic and analytical techniques, while hydrolytic reactivity towards a range of OP model compounds will be measured through colorimetric assays. Due to their enhanced safety profiles, these engineered enzymes would provide enhancements to conventional clinical interventions for acute OP exposures, especially when combined with post-exposure oxime treatments. In future work, these studies will be used to optimize BChE metalloenzymes that are effective against highly toxic and difficult-to-assay targets, for which evolutionary approaches are intractable, and ultimately develop effective formulations for storage and delivery for post-exposure indications. The goal of the introductory work proposed here is the initial development and validation of our experimental platform for designing and evaluating small sets of clinically relevant hybrid BChE metalloenzymes.

NIH Research Projects · FY 2025 · 2023-09

Project Summary As a urologic oncologist, most of my peers have focused on operating as much as possible with the hope their efforts could positively effect change on an individual level. During my NCI Urologic Oncology Fellowship, I was drawn to the power of clinical discovery working alongside clinical investigators. A surgeon has limited research paths to create paradigm shifts in the field beyond the operating room, as industry often ignores many of the critical questions facing us. Fortunately, the NIH Cooperative Group network trials provide an avenue for clinical scientists to impact the field by interacting with likeminded individuals, patient advocates, translational researchers, statisticians, and operational staff. By early engagement in SWOG, I have been afforded the opportunity to participate and lead several clinical trials before taking larger roles in translational research initiatives. This cemented my passion as a clinician scientist hoping to lead new initiatives in kidney cancer. I am fortunate to have assumed Co-Chair responsibilities within SWOG’s Renal Subcommittee and the NCI Renal Task Force. These leadership roles allow me to imprint the next generation of clinical trials. This also includes my involvement with a small renal mass trial aimed at reducing overtreatment, that was developed through a Clinical Trials Planning Meeting by much of the Renal Task Force and has been prioritized within SWOG this year with plans for GU Steering Committee review later this year. Despite receiving academic and leadership recognition, my engagement in NCI clinical research throughtrial participation, administrative efforts, mentorship of SWOG investigators, protocol development, and travel for bi-annual meetings, there is limited institutional support at UCLA for these endeavors. Similarly, the NCI sponsored trials have resulted in a financial burden to staff and this investigator, as compared to industry trials. Participation has largely been a result of my passion to provide patients an opportunity for improved care. The R50 Research Specialist Award mechanism recognizes the critical role that individuals can play to advance clinical science and can significantly advance my work. In particular, the financial support associated with this Award will further my engagement in available NIH protocols, provide time for protocol development including our new Small Renal Mass Concept, provide the means to travel to SWOG and Renal Task force meetings, and allow designated protected time that SWOG and Renal Task Force leadership requires. This Award would be instrumental in my academic career development during a time where the is increasing pressure to produce clinically. I am thrilled for this opportunity and appreciate UCLA recognizing my efforts with this nomination.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY African American (AA) men have the highest incidence and mortality rate from prostate cancer (PCa) in the United States. Prostate multi-parametric MRI (mpMRI) is a non-invasive imaging technique that can sensitively detect prostate tumors by integrating anatomical and functional information. The current standardized scheme for interpreting mpMRI is the Prostate Imaging Reporting and Data System (PI-RADS). However, detecting cancerous lesions currently does not account for racially associated MRI characteristics in PI-RADS. Our preliminary data showed a significant difference in detecting clinically significant PCa (csPCa) between AA and CA men using PI-RADS when the tumors are in the transition zone (67% vs. 80%, respectively, p=0.026). In addition, there was a distinctive difference in the PCa perfusion (that is, Ktrans) between AA and CA men, when measured by quantitative dynamic contrast-enhanced MRI (qDCE). When PI-RADS-based interpretation was combined with the Ktrans threshold value specified for AA men, the csPCa detection rate in the transition zone in AA men was improved to 76%, becoming not statistically different from that in CA men (p=0.180). We developed a point-of-care portable perfusion phantom named P4 to improve the reproducibility of qDCE measurement across different institutes. The P4-based error correction significantly reduced the variability in qDCE measurement across three MRI scanners in two institutes and improved the specificity of Ktrans for csPCa detection from 86% to 93%. We hypothesize that the racial disparity in PCa diagnosis can be reduced by using racially associated qDCE measurement after P4-based error correction. We propose to test this hypothesis in a multi-institutional setting at the University of California, Los Angeles (UCLA) and the University of Alabama at Birmingham (UAB). Our team will collect and link clinical, radiologic, and histopathologic information using patient-specific 3D-printed prostate molds, software registration, and expert annotation before and after radical prostatectomy. The highly curated radiology-pathology dataset will be used (1) to characterize the qDCE measurement associated with tumor microenvironment in AA and CA groups, using co-localized quantitative radiology-pathology analyses after P4-based error correction, (2) to investigate whether the racially associated MRI-based tissue characterization improves the detection of aggressive PCa, and (3) to develop the race/ethnicity-specific deep learning model for the improved detection of aggressive PCa. When the Aims are successfully accomplished, the improved detection of PCa in both AA and CA men is anticipated, compared to conventional strategies, reducing the racial disparity in detecting aggressive PCa.

NIH Research Projects · FY 2026 · 2023-09

Project Summary/Abstract For this application, “Mendelian imputation for family-based GWAS and association-by-proxy in diverse ancestries,” we propose to develop methods to enable more powerful estimation of family-based genome- wide association studies (GWASs) and apply these methods to a wide range of health, disease, and aging phenotypes in diverse populations. In brief, we propose to: · Meta-analyze family-based GWAS summary statistics on 30 phenotypes from 14 cohorts of predominantly European ancestry. In addition, through collaboration with the China Kadoorie Biobank and 23andMe, we will perform family-based GWAS in a set of diverse ancestries. Using the summary statistics, we will test within- and cross-ancestry prediction using polygenic indexes (PGIs, also called polygenic scores) derived from family-based and standard GWAS summary statistics, enabling us to determine the role of confounding in the drop in predictive accuracy of PGIs across ancestries. We will investigate methods that combine standard GWAS summary statistics and family-based GWAS summary statistics to improve polygenic prediction across ancestries. · Boost the power of family-based GWAS by adding genotyped individuals without any close relatives to the estimation sample. We will derive analytical formulas that can be used to quantify the efficiency gains in specific settings. We will develop an efficient linear mixed model algorithm that simultaneously performs standard- and family-based GWAS, maximizing power for both. Preliminary results from UK Biobank indicate this method results in an increase in effective sample size for estimation of direct genetic effects of between 30 and 40%. · Increase power for association-by-proxy methods by imputing relatives’ genotypes. Theory shows that power for discovery of associations could be increased when the genotype of the un-genotyped relative is imputed to give a more accurate estimate of the relative’s genotype. We will apply the methods to phenotypes available for UK Biobank participants’ parents, including Alzheimer’s disease and longevity. · Extend the algorithm for imputing parental genotypes to diverse populations and additional relatives. We will develop an algorithm that uses a diverse haplotype reference panel as the basis of pedigree- based imputation. In addition to removing bias from imputation in diverse samples, our approach will generalize the imputation algorithm to include relatives other than full-siblings and parents, thereby increasing imputation accuracy and power of downstream family-based genetic association analyses. The software for implementing the methods will be made publicly available on a GitHub repository. The summary statistics will be made publicly available to the maximum extent consistent with data use agreements.

NIH Research Projects · FY 2026 · 2023-09

SUMMARY Stem cell exhaustion is one of the key hallmarks of aging. In tissues throughout the body, there is a decline in stem cell number and function with age, leading to a loss of tissue homeostasis and regenerative capacity. Restoring youthful functionality to aged stem cells has been shown to improve the structure and function of aged tissues. As such, understanding the drivers of stem cell aging has the potential to reveal targets for rejuvenating tissue and even organismal aging. Despite the wealth of information on the phenotypic changes of stem cells with age, little is known about the underlying molecular mechanisms that drive those changes. Among those potential molecular mechanisms, we have explored genomic instability (another hallmark of aging) as a feature of aged stem cells. In the proposal, we propose that genomic instability and the accumulation of DNA damage underlie the age-related decline in stem cell number. Using muscle stem cells (MuSCs) as a model system, we have reported evidence of increases in DNA damage in aged MuSCs. This accumulation of DNA damage leads to an increased propensity of MuSCs to undergo a form of cell death called mitotic catastrophe when they attempt to enter the cell cycle when they are called upon to repair muscle. We found that this increased risk of cell death is associated with an age-related decrease in p53 activity, and that stabilizing or enhancing p53 reduces mitotic catastrophe and promotes muscle repair in aged mice. At the same time, we have found that that ATR, a key mediator of the DNA damage response (DDR), is highly active in quiescent MuSCs. The primary goal of the studies of this proposal are to explore the mechanistic relationship between two hallmarks of aging - genomic instability and stem cell exhaustion. Toward this goal, we will pursue three independent Specific Aims. In Aim 1, we will explore the role of p53 in the regulation of MuSC number during aging. We will use gain-of-function and loss-of-function genetic models to test this hypothesis. In Aim 2, we will examine the role of ATR in MuSC maintenance with age. These studies will include an unbiased phosphoproteomic screen to determine downstream mediators of ATR in MuSC maintenance. Aim 3 will focus on a p53 target gene, NDRG1, which has been shown to regulate genomic integrity in cancer cells under conditions of low proliferative states. In Preliminary Studies, we have found that NDRG1 slows MuSC activation, which is essential for the repair of DNA damage prior to cell division. We will examine the role of NDRG1 in MuSC activation during aging, again using gain-of-function and loss-of-function approaches. Together, these studies will advance our understanding of stem cell aging and highlight approaches to restore youthful function to aged stem cells as a way to enhance tissue homeostasis and repair in older individuals.

NIH Research Projects · FY 2025 · 2023-09

The shortwave infrared (SWIR) region of the electromagnetic spectrum has become an exciting avenue for imaging in mammals due to the increased penetration of light through tissue, decreased light scattering, and minimal autofluorescence. In the previous granting period, we showcased an additional advantage of the SWIR region– the enhanced spectral real estate which facilitates non-invasive multicolor imaging in mice. Taken together, all these advantages set the stage for: 1) fundamental biological studies in animal models analogous to those which have been enormously successful in cells and transparent organisms, 2) the ability to evaluate controls in same animal as the experimental group, and 3) advanced clinical diagnostics for both intraoperative and non-invasive use. While the SWIR region has great potential, it cannot be realized without biocompatible contrast agents. This proposal focuses on contrast agent development for high resolution multicolor imaging in the SWIR region, building on the expertise we have gained in polymethine fluorophores over the last granting period. We have prepared over 100 polymethine fluorophores and gained predictive metrics on the most classical photophysical parameters of lmax.abs, lmax,em and FF. We have also learned some key lessons regarding utility of the fluorophores including how to solubilize them in water and have gained appreciation for the different approaches to formulating fluorophores for imaging. In collaboration with the Bruns laboratory, we demonstrated excitation-based multicolor imaging with fluorophores well-matched to common laser lines. In the next granting period, we specifically focus on optimizing fluorophores for use in excitation-based multiplexing with detection in the high-resolution region of the SWIR (above 1400 nm) such that mm resolution can be achieved. Aim 1 explores the chromophore scaffold itself optimizing the photophysical properties for maximum absorption at commercial laser lines and emission >1400 nm. We take a physical organic chemistry approach to fluorophore optimization and capitalize on the continually growing, fully characterized set of systematically modified fluorophores our laboratory has prepared. Our work is aided by computation and theory collaborations with the Lopez and Caram Laboratories. Aim 2 transforms the lead fluorophores from aim 1 into water-soluble, targeted contrast agents. Finally in Aim 3, we aim image the lymphatic system, demonstrating the need for mm resolution imaging and then using excitation-based multicolor imaging to evaluate sentinel lymph node mapping and cancer metastasis.

NIH Research Projects · FY 2026 · 2023-09

Engineered T cells that express chimeric antigen receptors (CARs) have shown remarkable efficacy against hematological malignancies. However, broad implementation of CAR T cell therapies is limited by the lengthy (3–5 weeks) and costly ($350K–450K per treatment) ex vivo manufacturing pipeline. This proposal seeks to develop antigen-presenting nanoparticles (APNs) for in situ programming of virus-specific T cells for rapid and cost-efficient CAR T cell manufacturing. Virus-specific T cells present a promising opportunity to enhance CAR T cell therapy, as they have improved persistence and proliferation potential, and allow for viral vaccination to augment CAR therapy through their endogenous receptors. This proposal will focus on influenza A virus (IAV)- specific T cells to exploit the existing seasonal influenza vaccination to boost CAR activities. To deliver CAR to IAV-specific T cells, APNs will comprise lipid nanoparticles (LNPs) that encapsulate CAR-encoded mRNA and are decorated with HLA-A peptide-major histocompatibility complex (pMHC) displaying influenza peptide epitopes. This proposal will use APNs to deliver human B-cell maturation antigen (BCMA) CAR in the context of multiple myeloma with future goals to expand to other CAR specificities and indications, including CD19 positive cancers. The goal in Aim 1 is to develop APNs for transfection of human influenza-specific T cells with αBCMA CAR in vivo, and characterize the CAR transfection specificity in the target IAV-specific T cells versus other major cell populations. Aim 2 will be focused on validating the anti-cancer efficacy of αBCMA CAR T cells after in situ transfection using a mouse model recapitulating human multiple myeloma. The vaccination strategy to expand IAV-specific T cells and to boost their effector functions will be tested using inactivated influenza virions to vaccinate the CAR-expressing, IAV-specific T cells and compare the resulting anti-cancer potency with the unvaccinated cohort. In Aim 3, CRISPR/Cas9 will be implemented with APNs for in vivo gene editing of T cells with CAR for durable CAR expression and enhanced anti-cancer potency by delaying T-cell differentiation and exhaustion. The success of this proposal will challenge existing paradigms of T cell engineering, reduce the cost of CAR T cell therapy, and enhance anti-cancer activity through influenza vaccination to ultimately democratize CAR T cells for cancer therapy. Through this work, the candidate will close the knowledge gaps by the mentorship of an exceptional advisory committee: (1) Gabe Kwong, Ph.D. (CAR T cell engineering), (2) Phil Santangelo, Ph.D. (mRNA therapeutics and CRISPR/Cas), (3) Rafi Ahmed, Ph.D. (anti-viral T cell immunity and memory/exhaustion T cell biology), and (4) Madhav Dhodapkar, M.D. (hematology/oncology and myeloma cancer models). This strong mentoring team and the abundant resources provided by Georgia Tech and Emory University constitute a fertile mentoring environment for attaining the candidate's career goal of leading an independent research program focused on developing new technologies to improve patient access and treatment outcome of T-cell immunotherapy against cancer.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY This project aims to use human cortical organoids, which are cortex-like structures generated in vitro from human induced pluripotent stem cells (hiPSCs), to resolve outstanding questions in our understanding of causal mechanisms underlying the mesoscale phenomenology of anesthetic induction (AI) and anesthetic emergence (AE). Millions of patients undergo general anesthesia every year, but the mechanisms by which anesthetic drugs give rise to the hallmarks of AI remain unresolved. Even less well understood are the mechanisms by which the brain emerges from anesthesia - a process over which clinicians have almost no control, and which is frequently associated with complications such as emergence delirium, respiratory events, and delayed emergence, which results in prolonged hospital stays and increased cost of care. In addition, 1-2 per every 1000 patients will experience intraoperative awareness with explicit recall, for reasons that are not understood. While a number of hypotheses regarding the mechanisms of AI and AE have been put forward, these hypotheses are still debated because of complex inter-circuit interactions during AI and AE in the intact brain. In particular, it is widely believed that the major cause of AI is the potentiation of cortical GABAa receptors, but it has been difficult to disentangle the effects of cortical GABAa potentiation from the subcortical effects of anesthesia, which may likewise contribute to AI. Similarly, though it is generally believed that at least one, if not several cortically projecting neuromodulatory structures - including the histaminergic tuberomammillary nucleus of the hypothalamus, the cholinergic basal forebrain, the serotonergic raphe nuclei, the orexinergic lateral hypothalamus, and the noradrenergic locus coeruleus - directly drive emergence from anesthesia, these systems are densely interconnected and mutually excitatory. For this reason, in vivo research has been unable to resolve which, if any, of these systems directly cause AE. A promising but completely unexplored tool for resolving these questions are human cortical organoids. Our team has recently developed a protocol for fusing together networks of excitatory and inhibitory cortical-like neurons derived from hiPSCs. These fusion cortical organoids can recapitulate the oscillatory electric activity of the awake human cortex, and our preliminary results suggest that these cortical organoids can mimic the mesoscale hallmarks of AI when they are exposed to the anesthetic propofol. Importantly, cortical organoids consist of purely cortical- like human tissue, and lack any influence from subcortical structures or neuromodulatory systems. This allows us to use human cortical organoids to isolate cortical versus non-cortical causal mechanisms of both AI and AE. Successful modeling of AI and AE in brain organoids would illustrate the utility of these structures in high- throughput screening of novel drugs for inducing anesthesia or emergence from anesthesia, potentially even on a single-patient basis. Additionally, this project would establish the potential for human brain organoids in screening therapies for other states of unconsciousness, such as coma and persistent vegetative states.

NIH Research Projects · FY 2026 · 2023-09

ABSTRACT Education impacts health by improving access to socioeconomic resources and high-quality care (SES mechanism) and by improving literacy and numeracy, which aids in self-care and navigating the healthcare system (cognitive mechanism). But education does not just involve the acquisition of knowledge or cognitive skills. Education encompasses the experiences of being in a school environment, shaped by teachers, peers, and the “culture” of the school. Also referred to as school climate, these characteristics shape socioemotional factors that influence resilience and one's health trajectory (resilience mechanism). Almost all prior studies of education and health have relied on observational methods. In 2013, we began the Reducing Inequities through Social and Educational Change Follow-up (RISE Up) Study, a natural experiment using the admissions lottery of several high-performing public charter high schools to identify comparable groups of adolescents “randomized” into high- and lower-performing schools. We recruited students upon high school entrance and continue to follow this cohort currently (now age 22) with average annual retention rates of 96%. We found the impact of schools on self-reported health and health behaviors was immediate, substantial, and persistent beyond adolescence. By age 21, those who had attended a high-performing high school had a 50% lower rate of alcohol use disorder, 40% reduction in reporting fair or poor physical health, and 33% reduction in obesity/overweight. However, the improvements in physical health and obesity were only among males. Among females, attending a high-performing schools was associated with lower rates of alcohol use disorder, but substantially worse physical health and obesity. Surprisingly, intermediate academic outcomes (high school graduation, grade point average, test scores, and college matriculation) did not explain the impact of high-performing schools on substance use or physical health outcomes. Understanding how education influences health will inform the development of future interventions and school policies to make schools “healthier” for all students. Furthermore, our results to date are based on self-report. Thus, we proposed to follow the RISE Up cohort from age 23-28 to better understand how schools impact physiologic health perhaps through changes in socioemotional factors and resilience. We will measure blood pressure and body mass index and obtain blood samples to measure glycohemoglobin and C-reactive protein. We will examine epigenetic aging (DNA methylation), chronic stress (hair cortisol), and physiologic resilience using the Conserved Transcriptional Response to Adversity (CTRA). CTRA is a gene expression profile activated by fight-or-flight signaling from the sympathetic nervous system and related to greater inflammation and lower Type I interferon innate antiviral responses. Furthermore, we will explore sex differences in the relationship between education and physiologic health, stress, and resilience.

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY This proposal requests UH2/UH3 funding to build a collaborative research program to study Alzheimer’s disease (AD) and AD related dementias (ADRD) in diverse populations through the UCLA Health System in Los Angeles County. This program is led by a multi-disciplinary team with expertise in AD/ADRD clinical and neurobiological (PI Vossel, Co-I Chang); social and environmental (PI Mayeda); sociocultural (Co-I Díaz-Santos, Adrissi); and genomic (Co-I Chang, Deters) research. The program is based in the Mary S. Easton Center for Alzheimer’s Research and Care (Director Vossel), which has robust ties with greater L.A. communities and ongoing education and outreach activities. AD and ADRD comprise syndromes with a spectrum of environmental, social, genomic, and clinical mechanisms. To improve our understanding of the heterogeneity of AD/ADRD, individuals from all groups, including traditionally understudied groups, must be studied. The UCLA Health System serves one of the largest Hispanic/Latinx (HL), Black, and Asian American/Pacific Islander (AAPI) populations in the United States. Traditional AD/ADRD recruitment of these understudied populations has been challenging. Leveraging electronic health records (EHR) tools to recruit understudied populations and analyzing routinely collected EHR data would lower the barrier to entry. Our objective is to recruit HL, Black, and AAPI AD/ADRD cohorts via EHR tools and partnerships with primary care clinics and communities. Next, we will evaluate recruitment efficiency of EHR tools and partnerships, followed by augmentation of EHR with social determinants of health (SDOH), genetic, blood biomarker, neuroimaging, and neurophysiology data to study mechanisms of AD/ADRD in these understudied populations. Our long-term goal is to develop and scale an EHR-linked AD/ADRD research infrastructure in L.A. County through UCLA Health’s network sites, allowing integration of SDOH, neurobiological and genomic data. We will improve recruitment and retention of understudied ADRD populations in research by enrolling 160 HL, 160 Black, and 100 AAPI AD/ADRD individuals and controls. In preliminary work, our team has integrated dementia screening in the EHR to improve AD and ADRD diagnosis in primary care and studied genomic, social, and environmental risk factors of AD and ADRD from the EHR. During the UH2 phase we will 1) utilize EHR tools in HL, Black, and AAPI AD/ADRD participant recruitment, 2) engage HL, Black, and AAPI community partners to improve study recruitment and design, and 3) share clinical, social, and genomic data on NIA-supported infrastructures. During the UH3 phase we will 4) evaluate dementia screening and EHR tools on AD and ADRD recruitment in HL, Black, and AAPI individuals, 5) identify AD endophenotypes from social determinants of health, blood biomarker, neurophysiologic, and comorbidity factors in HL, Black and AAPI individuals, and 6) predict AD among HL, Black, and AAPI individuals using polygenic risk, SDOH, and comorbidities. This innovative program will support our goal is to discover personalized risk factors that will yield early behavioral interventions and precise therapies.

NIH Research Projects · FY 2026 · 2023-09

Project Abstract In response to NOT-21-039 and related PAR-22-093, we propose this project to address several urgent needs in the field. Mouse models spanning different ages and sexes are routinely used to quantify anatomic, molecular, and pathologic changes in neurodegenerative diseases like Alzheimer’s Disease (AD). Yet, the only available standard mouse brain atlases are constructed from 2-month-old adult male mice. Furthermore, although both normal aging and AD neurodegeneration display sexually dimorphic features, the scientific community lacks the sexually differentiated rodent brain atlases necessary to study these attributes. By applying cutting edge technologies, we have developed for BRAIN Initiative connectomic and cell type mapping projects, we will (1) generate sexually dimorphic 3D aging and AD brain atlases with granular hippocampus (HPF) molecular domains, that can be used as standard atlas templates for all HPF work and (2) we will comprehensively characterize morphological dystrophies, as well as connectional and synaptic disruptions, in aging and AD. In Specific Aim 1, publicly available standard 3D HPF atlases of aging and AD brains will be created. Data will be generated in 2-, 9-, and 18-month-old wildtype (WT), 5xFAD (early AD onset), and MAPT(H1)*N279K (late AD onset) male and female mice. Fine HPF domain delineations will be facilitated by 3D volumetric images of cyto- and myeloarchitecture, while additional histopathological markers (Aβ plaques/tau tangles) and chemoarchitectural details (glutamate, GABA, PV, SST, Calb1) will be mapped to create comprehensive histopathological and chemoarchitectural HPF atlases. In Specific Aim 2, We will systematically apply a genetic MORF3 sparse labeling approach to label, reconstruct, and analyze cell type specific neuronal morphology of all HPF regions at the granular level of their domains in WT, Vglut1.MORF3/5xFAD, PV.MORF3/5xFAD, Vglut1.MORF3/MAPT(H1)*N279K, and PV.MORF3/MAPT(H1)*N279K mice across age and sex. Our whole brain 3D clearing, immunostaining, imaging, and 3D neuronal reconstruction pipeline will be applied. Given that an etiology of AD-related cognitive decline is selective HPF synaptic disruptions, with dorsal HPF nodes being some of the earliest affected in AD, in Specific Aim 3, will examine progressive connectional disruptions along amyloid and tau pathology progression. Male and female MORF3 and double transgenic mice, MORF3/5xFAD and MORF3/MAPT(H1)*N279K, at 2m, 9m, and 18m of age will be used to reveal potential connectivity changes across aging and AD. The same groups will be used to determine synaptic-level HPF disruptions with the application of Expansion Microscopy that will capture super-resolution images of synaptic connections. In Specific Aim 4, we will create a web-based data portal that enables visualization, comparison, and analysis of neural circuits and cell types in 3D aging and AD brains. Our team, with decades of experience in connectomics, brain atlasing, and online visualization, is sure to deliver standard HPF atlas templates for all neuroscience research and to determine sexually dimorphic anatomic regions vulnerable across age and AD progression.

NIH Research Projects · FY 2024 · 2023-09

NIH Research Projects · FY 2025 · 2023-09

Abstract In the Hospital of the Future hospitalization will be reserved almost exclusively for patients with severe acute illness, staff numbers will be reduced, and hospitals will be built around smart environments that facilitate consistent delivery of effective, equitable, and error-free care focused on patient-centered rather than provider- centered outcomes. This is particularly relevant to the surgical population. While ambulatory surgical centers are the fastest growing providers, more than 51 million inpatients procedures are performed annually in hospitals in the US and inpatient surgery centers are taking care of sicker and older patients. While intraoperative mortality is rare due to improvements in surgical techniques, anesthesia management, and intraoperative monitoring, global postoperative mortality remains the third leading cause of death among American People. Recent studies have shown that while the incidence of postoperative major complications after major surgery is similar between hospitals (~25%), the postoperative mortality following postoperative major complications from one hospital to the other can be up to 2.5-fold higher. This suggests that reducing variations in mortality following major surgery will require strategies to improve the ability of high-mortality hospitals to manage postoperative major complications and decrease failure-to-rescue. One of the solutions identified is to leverage Health Information Technologies. The goal of this proposal is to use machine learning approaches to develop, validate, and test real-time postoperative risk prediction tools based on multi-modal data sources using electronic health record data, high-fidelity physiological waveform features, and genomic data to identify patients who are at risk of developing postoperative major complications after surgery. Using extensive electronic health record derived annotation augmented with high-fidelity physiological waveform features and genomic data and applying state-of-the-art machine learning approaches, common patterns in subjects destined to develop postoperative major complications and those at very low risk of developing postoperative major complications after surgery will be characterized and quantified. These inputs will then be used in simulated real-time bedside management to iteratively design a prototype clinical decision support tool. This clinical decision support tool will be used at discharge from the post anesthesia care unit to identify surgical patients who will benefit from continuous remote monitoring and early warning system on the ward to prevent postoperative failure to rescue. The feasibility and acceptability of this approach will then be assessed in a small-scale prospective, longitudinal pilot evaluation in sequential 10-weeks, 13-weeks, 10-weeks phases at UCLA to help design a future, large-scale clinical trial.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY / ABSTRACT The goal of this proposal is to leverage molecular neuroscience techniques to define the role of oxygen (O2) as a biologically relevant chemosensory cue in the human-infective threadworm Strongyloides stercoralis. Globally, S. stercoralis infects ~610 million people, with a high disease burden in resource-poor settings. Strongyloidiasis, considered an emerging and/or re-emerging disease, can manifest as an indolent multi-decade gastrointestinal infection; immunocompromised individuals are at high risk of hyperinfection syndrome and disseminated disease – of which most cases are fatal. Given the threat of anthelmintic resistance, novel chemotherapeutic strategies are needed to treat and cure individuals with strongyloidiasis. Parasitic nematodes rely upon neuronally detected sensory cues to actively seek hosts, navigate intra- and extra-host environments, and coordinate their development with their local context. S. stercoralis, as a soil- transmitted helminth, thrives in O2 concentrations that range from atmospheric levels (~21%) at the soil surface to near-anaerobic conditions in the host intestinal tract. However, O2 sensation remains completely unstudied in S. stercoralis or any other parasitic nematode. This proposal hypothesizes that the neural and molecular machinery mediating O2 sensation in S. stercoralis may yield promising targets vulnerable to intervention. This proposal will explore O2 sensation in S. stercoralis at the behavioral, neuronal, and molecular levels. The first aim of this proposal seeks to characterize how O2 serves as a chemosensory cue to sculpt the motile behaviors of S. stercoralis throughout its parasitic life cycle. Quantitative analysis of parasite behaviors in different O2 contexts will be performed. Additionally, work proposed in the first aim will interrogate the role of shifting O2 levels as a developmental cue that enables parasitism. In the second aim of this proposal, chemogenetic neuronal silencing and calcium imaging techniques will be employed to both identify O2-sensing neurons and describe parasite-specific encoding properties in these neurons. In the proposal’s third aim, CRISPR/Cas9-mediated mutagenesis and ectopic expression systems will be used to determine the molecular sensors of O2 in S. stercoralis and explore their mechanism of action. This proposal will generate new insights into parasite chemosensory neurobiology and may reveal novel strategies for preventing nematode infections. This proposal will support the applicant’s goal of becoming a physician-scientist dedicated to the study and clinical management of parasitic infectious diseases. In completing the proposed aims, the applicant will augment prior training in parasitology and molecular biology with the development of new skills in neuroscience research. This work will be performed in one of the only laboratories studying neurobiology in parasitic nematodes; the applicant will also seek mentorship from the rich community of parasitologists and neuroscientists at UCLA.

NIH Research Projects · FY 2024 · 2023-09

Methods for bond construction enabling the synthesis of complex molecular scaffold are of key interest to the pharmaceutical industry. To this end, Ni catalysis has emerged as a versatile tool for the construction of C(sp2)– C(sp2), C(sp3)–C(sp2), and C(sp3)–C(sp3) bonds. The success of Ni in accomplishing these transformations lies in the ability of Ni to engage in both single- and two-electron processes – cycling through 0, I, II, and III oxidation states. As a result, in addition to canonical two-electron processes (migratory insertion, b-hydride elimination, etc.), fundamental steps such as abstractions, radical captures, and electron transfers are often encountered in Ni catalysis. Ni catalysis has also served as a fruitful platform for the integration of photochemistry in transition- metal catalysis. Recently, our group found that upon irradiation with light, aryl NiII(bpy) complexes can undergo excited-state bond homolysis to generate C(sp2) radicals. These initial stoichiometric studies demonstrate that light energy can be selectively directed to Ni to generate highly reactive intermediates from feedstock chemical precursors. We propose leveraging photoelimination from NiII as a general step to be employed in Ni catalysis. Traditional development of cross-coupling reactions focuses around achieving new outcomes from sequences of known fundamental processes. This proposal is unique as it is based on the development of a new fundamental step for Ni catalysis. Our efforts will capitalize on the interplay between single- and two- electron processes accessible to Ni to address limitations in selectivity and reactivity in the present literature. The research described herein will be comprised of three aims: (1) developing approaches for improving quantum yield of excited-state Ni bond homolysis processes, (2) explore and extend the scope of organic radical centers accessed by photoelimination, and (3) employing photoelimination as fundamental step in Ni catalysis. All three aspects will be explored concurrently and together represent an exciting new direction in the field of first-row transition metal catalysis.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Advances in breast cancer treatment have resulted in significant survival gains. However, cure or control of breast cancer is not necessarily accompanied by full restoration of health. We have shown that as breast cancer survivors age, they experience accelerated chemotherapy-induced functional decline compared to age-matched survivors not treated with chemotherapy and women without cancer. Chemotherapy-induced functional decline results in poor quality of life, loss of independence, and premature death. The proposed study builds on our clinical work showing that cellular senescence is a central process linked to chemotherapy-induced functional decline. Cellular senescence is a fundamental aging process characterized by cell cycle arrest. Senescent cells accumulate in aging tissues and secrete proinflammatory factors that drive age-related functional decline. We have observed that, in breast cancer survivors, chemotherapy induces the persistent presence of high levels of circulating senescent cells, and that survivors with high senescent cell burden are more likely to experience chemotherapy-induced fatigue, neuropathy, and functional decline. These data provide rationale for targeting and reducing senescent cells to alleviate chemotherapy-induced functional decline. In non-cancer populations, senescent cells can be reduced through use of exercise or senolytics (drugs that ablate senescent cells). Recent preclinical studies also showed that senolytics combined with exercise yielded a greater reduction in senescent cells compared to either intervention alone. However, the ability of exercise and senolytics to reduce senescent cells and, ultimately, improve physical function in breast cancer survivors has not been tested. We hypothesize that targeting senescent cells via exercise and senolytics in breast cancer survivors will yield independent and additive effects to improve physical function and reduce markers of biological aging. To test this hypothesis, we propose a multicenter randomized placebo-controlled trial to test the efficacy of exercise and senolytic therapy (alone or combined) on physical function and markers of biological aging. We will randomize chemotherapy- treated postmenopausal breast cancer survivors with diminished function, assessed using the 6-minute walk distance [6MWD], to 1 of 4 arms: exercise + senolytic; exercise alone; senolytic alone; or control. The primary endpoint will be the change in 6MWD from baseline to end of treatment (Aim 1). Secondary endpoints include clinical and biological aging markers (Aim 2). We also will assess the safety and adherence of both interventions. In summary, as the number of breast cancer survivors rises dramatically (estimated to be >6 million by 2040), mitigating chemotherapy-induced functional decline is an urgent public health issue and a priority of the NIH. Successful completion of this trial will establish the efficacy of two targeted treatments to mitigate chemotherapy- induced functional decline. Given that senescence underlies many mid- and late-life chronic diseases, a safe treatment that improves physical function would have a major positive impact that extends far beyond oncology.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY This proposal requests UH2/UH3 funding to build a collaborative research program to study Alzheimer’s disease (AD) and AD related dementias (ADRD) in diverse populations through the UCLA Health System in Los Angeles County. This program is led by a multi-disciplinary team with expertise in AD/ADRD clinical and neurobiological (PI Vossel, Co-I Chang); social and environmental (PI Mayeda); sociocultural (Co-I Díaz-Santos, Adrissi); and genomic (Co-I Chang, Deters) research. The program is based in the Mary S. Easton Center for Alzheimer’s Research and Care (Director Vossel), which has robust ties with greater L.A. communities and ongoing education and outreach activities. AD and ADRD comprise syndromes with a spectrum of environmental, social, genomic, and clinical mechanisms. To improve our understanding of the heterogeneity of AD/ADRD, individuals from all groups, including traditionally understudied groups, must be studied. The UCLA Health System serves one of the largest Hispanic/Latinx (HL), Black, and Asian American/Pacific Islander (AAPI) populations in the United States. Traditional AD/ADRD recruitment of these understudied populations has been challenging. Leveraging electronic health records (EHR) tools to recruit understudied populations and analyzing routinely collected EHR data would lower the barrier to entry. Our objective is to recruit HL, Black, and AAPI AD/ADRD cohorts via EHR tools and partnerships with primary care clinics and communities. Next, we will evaluate recruitment efficiency of EHR tools and partnerships, followed by augmentation of EHR with social determinants of health (SDOH), genetic, blood biomarker, neuroimaging, and neurophysiology data to study mechanisms of AD/ADRD in these understudied populations. Our long-term goal is to develop and scale an EHR-linked AD/ADRD research infrastructure in L.A. County through UCLA Health’s network sites, allowing integration of SDOH, neurobiological and genomic data. We will improve recruitment and retention of understudied ADRD populations in research by enrolling 160 HL, 160 Black, and 100 AAPI AD/ADRD individuals and controls. In preliminary work, our team has integrated dementia screening in the EHR to improve AD and ADRD diagnosis in primary care and studied genomic, social, and environmental risk factors of AD and ADRD from the EHR. During the UH2 phase we will 1) utilize EHR tools in HL, Black, and AAPI AD/ADRD participant recruitment, 2) engage HL, Black, and AAPI community partners to improve study recruitment and design, and 3) share clinical, social, and genomic data on NIA-supported infrastructures. During the UH3 phase we will 4) evaluate dementia screening and EHR tools on AD and ADRD recruitment in HL, Black, and AAPI individuals, 5) identify AD endophenotypes from social determinants of health, blood biomarker, neurophysiologic, and comorbidity factors in HL, Black and AAPI individuals, and 6) predict AD among HL, Black, and AAPI individuals using polygenic risk, SDOH, and comorbidities. This innovative program will support our goal is to discover personalized risk factors that will yield early behavioral interventions and precise therapies.